Acetaminophen is a widely used analgesic and antipyretic, which can cause liver injury after an overdose. Although a controversial topic for some time, solid evidence for a critical role of oxidative and nitrosative stress has emerged during the last two decades. This review will discuss the cellular sources, amplification mechanisms and the consequences of the excessive formation of reactive oxygen and nitrogen species in the clinically relevant mouse model of acetaminophen hepatotoxicity. This new mechanistic insight contributes to the better understanding of the mechanism of action of N-acetylcysteine, the only clinically approved antidote. In addition, it provides the rationale for the development of new antidotes that target the formation or metabolism of mitochondrial superoxide.
Keywords: 4-methylpyrazole; Acetaminophen hepatotoxicity; c-jun N-terminal kinase; calmangafodipir; lipid peroxidation; mitochondrial oxidant stress.